PROJECT SUMMARY/ABSTRACT Multiple sclerosis (MS) is an inflammatory demyelinating neurologic disorder thought to be caused by immune-mediated injury against the central nervous system (CNS). The adaptive immune system, in particular, is considered to be a central mediator of MS immunopathogenesis. B cells and CD4+ T cells have historically received greater focus in MS research. CD8+ T cells are best known for their cytotoxic function in viral and tumor immunity, yet compelling evidence suggests an important, but still largely unknown role in MS. I am seeking a K08 Mentored Clinical Scientist Research Career Development Award in order to gain the experience and expertise needed to advance our understanding of T cells in MS. The goal of this K08 application is to delineate which CD8+ T cells are likely important in MS. Two parallel, complementary aims are proposed to achieve this goal. In Specific Aim 1, novel myelin CD8+ T cell epitopes will be identified and characterized in order to test the hypothesis that myelin-reactive CD8+ T cells are more abundant and pro- inflammatory in MS patients compared to control subjects. In Specific Aim 2, CD8+ T cells isolated from the blood and cerebrospinal fluid (CSF) will undergo high throughput next generation sequencing. This aim will test the hypothesis that the CD8+ T cell repertoire in MS patients is less diverse compared to control subjects and CD4+ T cells owing to intrathecal CD8+ T cell clonal expansion. The two aims will be bridged by sequencing the TCR repertoire of myelin-reactive CD8+ T cells from the blood in order to search for myelin-specific clonotypes in the CSF of MS patients. Elucidation of which CD8+ T cell populations are relevant to MS will pave the way toward determining their role in the disease. My long-term goal is to significantly advance our understanding of MS pathogenesis and hopefully provide guidance for novel therapeutic strategies. As I transition to Assistant Professor, I have assembled an outstanding team of mentors and advisors to guide me towards becoming an independent investigator. The research environment at UCSF is unparalleled and offers access to world-class faculty and researchers in the fields of Neurology and Immunology as well as cutting-edge equipment and research facilities, including at the Sandler Neurosciences Building and Center for Advanced Technology where my work will be completed. With the support of my mentors, institution, and the K08 Career Development Award, I am confident I will be well positioned to transition to an independent research career with R01 or equivalent funding by the end of my five-year training plan.